Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain

A Multicenter, Blinded, Randomized, Placebo-Controlled, Dose-Ranging Influenza Challenge Study in Healthy Adult Volunteers to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2), Clade 3C3a) Influenza Challenge Virus

An open-label, dose-ranging influenza challenge study in healthy adult volunteers to determine the optimal infection dose and safety of a recombinant H3N2 (A/Texas/ A/Texas/71/2017 (H3N2, clade 3C3a) influenza strain. The goal of this study is to find a challenge virus dose that is safe and can achieve a symptomatic influenza Attack Rate (AR) that will be sufficiently high for utilization in future vaccine or intervention studies. The optimal dose of the three considered is broadly defined as the minimum challenge virus dose that elicits the highest AR without meeting safety-stopping criteria. Additionally, viral recovery, clinical symptoms, and immune responses over the post-challenge period will be described by challenge dose group. This study will last for up to 1 year depending upon the number of challenge cohorts enrolled given the adaptive dose-escalation design. The populations are healthy males and non-pregnant, non-breastfeeding females aged = 18 and < 46 years of age with a serum HAI antibody titer of </=1:40 against influenza A/Texas/71/2017 (H3N2), clade 3C3a. The study will enroll and challenge up to 106 (plus 8 shams) healthy adult volunteers with the H3N2 (A/Texas/71/2017 (H3N2), clade 3C3a) influenza virus challenge strain. The primary objectives are: 1) To determine the optimal infectious dose of a recombinant influenza virus (A/Texas/71/2017 (H3N2), clade 3C3a) to be used as a clinical challenge strain in future vaccine efficacy or intervention studies as assessed by viral shedding and clinical symptoms. 2) To describe viral detection by quantitative and qualitative Reverse Transcription - Polymerase Chain Reaction (RT-PCR) from study subjects at baseline and post-challenge. 3) To document clinical symptoms from self-reported surveys and standardized symptom scales at baseline and post-challenge.

An open-label, dose-ranging influenza challenge study in healthy adult volunteers to determine the optimal infection dose and safety of a recombinant H3N2 (A/Texas/ A/Texas/71/2017 (H3N2, clade 3C3a) influenza strain. The goal of this study is to find a challenge virus dose that is safe and can achieve a symptomatic influenza Attack Rate (AR) that will be sufficiently high for utilization in future vaccine or intervention studies. The optimal dose of the three considered is broadly defined as the minimum challenge virus dose that elicits the highest AR without meeting safety-stopping criteria. Additionally, viral recovery, clinical symptoms, and immune responses over the post-challenge period will be described by challenge dose group. This study will last for up to 1 year depending upon the number of challenge cohorts enrolled given the adaptive dose-escalation design. The populations are healthy males and non-pregnant, non-breastfeeding females aged = 18 and < 46 years of age with a serum HAI antibody titer of </=1:40 against influenza A/Texas/71/2017 (H3N2), clade 3C3a. The study will enroll and challenge up to 106 (plus 8 shams) healthy adult volunteers with the H3N2 (A/Texas/71/2017 (H3N2), clade 3C3a) influenza virus challenge strain. Subjects will be pre-screened for study inclusion to have serological HAI antibody titers of </=1:40 against the clinical challenge strain. Eligible participants will be enrolled sequentially into dosing cohorts and will be randomly assigned to receive a single dose of either placebo (sham inoculum) or a virus dose between 104 to 106 Median Issue Culture Infectious Dose (TCID50) (in an allocation of 1:12 to 1:17). Dose titration will be conducted under an adaptive escalation schedule whereby dosing will start at the lowest dose 104 TCID50 and only escalate to the next dose if a pre-determined infection and symptomatic attack rate are not met and the dose is determined to be safe and no pre-defined halting rule is met. The attack rate (AR), defined as the percentage of subjects meeting shedding and symptom criteria for symptomatic influenza virus infection (see clinical case definition below), will be determined for each challenge dose group in order to identify the optimal infectious dose (55%-80% AR). This adaptive, dose-ranging approach allows adjustments to challenge dose group size and escalation dose schedule to be informed by the AR and safety results. The primary objectives are: 1) To determine the optimal infectious dose1 of a recombinant influenza virus (A/Texas/71/2017 (H3N2), clade 3C3a) to be used as a clinical challenge strain in future vaccine efficacy or intervention studies as assessed by viral shedding and clinical symptoms. 2) To describe viral detection by quantitative and qualitative Reverse Transcription - Polymerase Chain Reaction (RT-PCR) from study subjects at baseline and post-challenge. 3) To document clinical symptoms from self-reported surveys and standardized symptom scales at baseline and post-challenge. The secondary objectives are: 1) To assess the safety profile of a live recombinant influenza strain (A/Texas/71/2017 (H3N2), clade 3C3a) following challenge in healthy adult volunteers. 2) To describe the host serum hemagglutination inhibition and microneutralization antibody responses at baseline and post-challenge. 3) To describe anti-Hemagglutination(HA)-stalk antibody titer at baseline and post-challenge.

Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedure

2. Are able to understand and comply with planned study procedures and be available for all study visits

3. Agree to remain an inpatient for at least 7 days after challenge AND until they have no viral shedding*, determined by qualitative Reverse Transcription - Polymerase Chain Reaction (RT-PCR) beginning on Study Day 6

   • No viral shedding is defined as two negative RT-PCR tests 12 or more hours apart

4. Healthy* males and non-pregnant, non-breastfeeding females aged > / = 18 and < 46 years of age at enrollment

   *Healthy is defined in inclusion criteria #11. NOTE: Female subjects of childbearing potential must have a negative serum pregnancy test at screening, a negative urine pregnancy test upon admission to the confinement unit AND a negative pregnancy test before any Chest x-ray (CXR) (if > / = 7 days have passed since a serum pregnancy test).

5. Women of childbearing potential* must agree to use or have practiced true abstinence** or use at least one acceptable primary form of contraception* for at least 30 days prior to challenge

   • Not of childbearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure(R) placement with history of documented radiological confirmation test at least 90 days after the procedure).

   • True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

     • Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the influenza challenge virus, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products. Must use at least one acceptable primary form of contraception for at least 30 days prior to challenge and at least one acceptable primary form of contraception during the remainder of the study or approximately 57 days after confinement.

   NOTE: These criteria are applicable to female subjects in a heterosexual relationship AND of child-bearing potential. These criteria do not apply to subjects in a same sex relationship.

6. Non-habitual smoker* of tobacco, e-cigarettes or marijuana

   *Non-habitual smokers are those who smoke no more than four cigarettes, other tobacco products, e-cigarettes (to include vaping and Juuling products) or marijuana in a week and agree not to smoke cigarettes, other tobacco products, e-cigarettes and/or marijuana products during participation in the study.

7. No self-reported or known history of alcoholism within the last 2 years and agrees to abstain from alcohol for at least one week before admission and throughout the confinement period.

8. No self-reported or known history of restricted drug use* for at least 30 days prior to challenge and agrees to abstain from restricted drugs for at least one week before admission and throughout the confinement period

9. Negative drug urine toxicology result on screening (i.e., amphetamines, cocaine, and opiates) and on admission to the confinement unit (i.e., amphetamines, cocaine, and opiates)*

   *Select drug use may be allowed at Investigator's discretion (e.g., prescribed amphetamines for ADHD)

10. Agree not to use the listed prescription or over the counter medications* within 7 days prior to and through confinement period, unless approved by the investigator

    *Oseltamivir, zanamivir, peramivir, baloxavir marboxil, amantadine (generic) and rimantadine (Flumadine and generic), aspirin, intranasal steroids, decongestants, antihistamines, and other non-steroidal anti-inflammatory drugs (NSAIDs)

11. In good health*, and do not have clinically significant medical, psychiatric, chronic or intermittent health conditions including those listed in Exclusion Criteria

    *Good health, as determined by medical history, medication use and physical examination to evaluate ongoing chronic medical or psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would not affect the assessment of the safety of subjects or the immunogenicity of challenge. These medical diagnoses or conditions should be stable for the last 90 days (no hospitalizations, emergency room (ER) or urgent care for condition (excluding musculoskeletal conditions) and not listed in Exclusion Criteria. Subjects may be on medications only if the condition or disease is stable and not deteriorating, if the medical intervention (such as device or medication) was not available during the maximal inpatient period of time, medications are not listed in the Exclusion Criteria and pose no additional risk to subject safety or assessment of adverse events. This also includes no change in prescription medication, dose or frequency as a result of new symptoms or deterioration of the medical diagnosis or condition in the 90 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome (e.g., lowering of the dosage or frequency), as determined by the site principal investigator (PI) or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572, will not be considered a deviation of this inclusion criterion.

12. Vital signs as follows:

    • Pulse is 47 to 99 beats per minute, inclusive
    • Systolic blood pressure is 85 to 139 mmHg, inclusive
    • Diastolic blood pressure is 55 to 89 mmHg, inclusive
    • Saturation of Peripheral Oxygen (SpO2) >/= 95%; Respiratory Rate (RR) </= 18
    • Oral temperature is less than 100.6 degrees Fahrenheit

13. Eligibility laboratory values White Blood Cell (WBC), Absolute Lymphocyte Count, Hemoglobin (Hgb), Platelets (PLTs), Alanine Transaminase (ALT) and Creatinine(Cr) are within acceptable parameters*

    *Labs within normal range or grade 1 abnormalities deemed not clinically significant by a study investigator are considered acceptable

14. Body mass index (BMI) > 18.5 and < 40 kg/m2 at screening

15. Other screening tests Electrocardiogram (ECG) and Chest x-ray(CXR) are within normal reference range or not deemed clinically significant by the Principle Investigator(PI) or appropriate sub-investigator*

    *Designated clinician licensed to make medical diagnoses and listed on the Form FDA 1572

16. Negative test for Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) at screening

17. Negative respiratory virus panel by BIOFIRE(R) FILMARRAY(R) respiratory panel by bioMérieux or by Luminex xTAG(R) on Day -2, and Day -1

18. Negative RT-PCR test for severe acute respiratory syndrome coronavirus 2(SARS-CoV 2) on screening and Day -2

19. Hemagglutination Inhibition Test (HAI) antibody titer </=1:40 against influenza A/Texas/71/2017 (H3N2) at screening

20. Receipt of the recommended number of doses of an (Emergency Use Authorization) EUA authorized or licensed coronavirus disease of 2019 (COVID-19) vaccine product = two weeks prior to confinement

Exclusion Criteria:

1. Presence of self-reported or medically documented significant medical or psychiatric condition(s)*

   *Significant medical or psychiatric conditions include but are not limited to:

   1. Respiratory disease (e.g., chronic obstructive pulmonary disease [COPD], asthma) requiring daily medications [Inhaled, oral or intravenous (IV) corticosteroids, leukotriene modifiers, long and short acting beta agonists, theophylline, ipratropium, biologics] or any treatment for respiratory disease exacerbations (e.g., asthma exacerbation) within the last 5 years
   2. Presence of any febrile illness or symptoms suggestive of a respiratory infection within two weeks prior to challenge
   3. Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart disease) or history of myocarditis or pericarditis as an adult.
   4. Neurological or neurodevelopmental conditions (e.g., epilepsy, stroke, seizures, encephalopathy, focal neurologic deficits, Guillain-Barre syndrome, encephalomyelitis or transverse myelitis).
   5. Ongoing malignancy or recent diagnosis of malignancy in the last five years (excluding basal cell carcinoma of the skin)
   6. Presence of an autoimmune disease.
   7. Immunodeficiency of any cause.
   8. History of diabetes.

2. Presence of immunosuppression or any medications that may be associated with impaired immune responsiveness*

   *Including, but not limited to, corticosteroids exceeding 10 mg/day of prednisone equivalent, allergy injections, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or systemic corticosteroids or other similar or toxic drugs during the preceding 12-month period prior to screening. Low dose topical and intranasal steroid preparations used for a discrete period of time are permitted.

3. Known allergy or intolerance to treatments for influenza (including any neuraminidase inhibitors or baloxavir marboxil).

4. Known allergy to two or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).

5. Known allergy to excipients* in the challenge virus inoculum.

   *Sucrose, KH2PO4, K2HPO4, L-glutamic acid (in SPG diluent)

6. Receipt or planned receipt of any investigational drug/investigational vaccine/licensed vaccine, except for a licensed or emergency use authorized coronavirus disease of 2019 (COVID-19) vaccine product, within 30 days prior to the date of challenge.

7. Prior enrollment in an influenza virus challenge study with an influenza virus of the same subtype within the past 2 years.

8. Currently enrolled in any investigational study or intends to enroll in such a study within the ensuing study period.*

   *Co-enrollment in an observational study, an investigational study in a follow-up/post-vaccination stage, or a study involving a licensed drug or biologic may be allowed at the investigator's discretion.

9. Receipt of any influenza vaccine four months prior to challenge or plans to receive influenza vaccine during the study (approximately 57 days after challenge).

10. History of a previous severe allergic reaction to any drug or biologic with generalized urticaria, angioedema, or anaphylaxis.

11. Receipt of blood or blood products during the six months prior to the planned date of challenge.

12. Plans to donate blood or blood products during the study. (approximately 102 days).

13. Any condition (including medical and psychiatric conditions) that, in the opinion of the Investigator, might interfere with the safety of the subject and/or study objectives.

14. An ongoing symptomatic condition for which subject has had or has ongoing medical investigations but has not yet received a diagnosis or treatment plan e.g., ongoing fatigue without a diagnosis.

15. Known close contact with anyone known to have or suspected to have a respiratory viral illness within 7 days prior to challenge.

16. Significant abnormality altering anatomy of nose/nasopharynx (including significant nasal polyps), clinically significant nasal deviation, or nasal/sinus surgery within 180 days prior to challenge.

17. History in the last five years of chronic or frequent intermittent sinusitis.

18. Recent history (180 days) of epistaxis or anatomic or neurologic abnormality impairing the gag reflex or contributing to aspiration.

19. Currently using an internal cardiac device such as a pacemaker or other implanted electronic medical devices.